化学
秋水仙碱
芳基
微管蛋白
组合化学
立体化学
微管
有机化学
医学
生物
细胞生物学
内科学
烷基
作者
Hao Chen,Shanshan Deng,Najah Albadari,Mi‐Kyung Yun,Sicheng Zhang,Yong Li,Dejian Ma,Deanna N. Parke,Lei Yang,Tiffany N. Seagroves,Stephen W. White,Duane D. Miller,Wěi Li
标识
DOI:10.1021/acs.jmedchem.1c00715
摘要
We previously reported a potent tubulin inhibitor CH-2-77. In this study, we optimized the structure of CH-2-77 by blocking metabolically labile sites and synthesized a series of CH-2-77 analogues. Two compounds, 40a and 60c, preserved the potency while improving the metabolic stability over CH-2-77 by 3- to 4-fold (46.8 and 29.4 vs 10.8 min in human microsomes). We determined the high-resolution X-ray crystal structures of 40a (resolution 2.3 Å) and 60c (resolution 2.6 Å) in complex with tubulin and confirmed their direct binding at the colchicine-binding site. In vitro, 60c maintained its mode of action by inhibiting tubulin polymerization and was effective against P-glycoprotein-mediated multiple drug resistance and taxol resistance. In vivo, 60c exhibited a strong inhibitory effect on tumor growth and metastasis in a taxol-resistant A375/TxR xenograft model without obvious toxicity. Collectively, this work showed that 60c is a promising lead compound for further development as a potential anticancer agent.
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